Cefaclor:Chemistry and Pharmacology,Pharmacokinetics

Introduction

Cefaclor, a congener of cephalexin, is a second-generation oral cephalosporin β-lactam antibiotic and was certified for clinical use in 1979 by the United State Food and Drug Administration (US FDA). It is effective against gram-positiveand gram-negative bacteria. It treats acute otitis media, pharyngitis, tonsillitis, urinary tractinfection (UTI), skin and soft tissue infection, and upper and lower respiratory tractinfections. It has a high affinity for penicillin-binding proteins(PBPs), causing the inhibition of the terminal transpeptidation step of bacterial cell wall synthesis, thus arresting cell wall assembly resulting in bacterial cell lysis. The available oral dosage forms of cefaclor aretablet (500 mg), powder for oral suspension (125 mg/5ml, 250 mg/5ml, and 375 mg/5ml),and capsule form (250 mg, 500 mg).[1]

Chemistry and Pharmacology

Cefaclor is a β-lactam antibiotic whose chemical formula is C₁₅H₁₄ClN₃O₄S, and its molecular weight is 367.808g/mol. The physical appearance of cefacloris a white to cream color solid crystalline powder (Figure.1). Cefaclor exhibits low solubility in water and is nearly insoluble in chloroform, ether, and benzene. Being a weak acid, its pKa value is 1.5–7.2. The solubility of cefaclor in water is 10mg/ml at 25°C. Cefaclor exists in three salt forms: monohydrate, hydrochloride,and free form. Despite these differences in salt forms, there appears to be no significant variance in solubility among cefaclor, and cefaclor monohydrate, while the remaining salts are unidentified.[1]

Cefaclor is closely related structurally to cephalexin; the methyl group of cephalexin has simply been substituted with a chlorine atom. (Cephalexin is marketedas the monohydrate salt; cefaclor is not.) This chlorine substitution results in somewhat altered antibacterial activity and pharmacokinetic properties. The mechanism of action is the same as that of the other β-lactam antibiotics.It is thought that these antibiotics inhibit peptidoglycan synthesis by binding to specific proteins of the cell wall and consequently exert a bactericidal effect by activation of autolysins in sensitive bacteeria.[2]

Pharmacokinetics

Cefaclor shows the linear PK profile as the area under the plasma concentration-time curve from 0 to t (AUC_0-t) and maximum plasma concentration (Cmax) increase in a dose-dependent manner. The AUC_0-t of cefaclor in the rice diet was found to be higher than that of bread food, i.e.19.9±2.6 ug/ml.hr vs 15.4±4 ug/ml.hr. The AUC in paediatrics during the fed state was significantly higher compared to that in adults. Patients with renal impairments showed a Cmax 2.2 times higher than that of normal subjects. A significant increase in Cmax was depicted among individuals following a vegetarian diet in comparison with the non-vegetarian diet. Moreover, cefaclor exhibits time-dependent killing above the minimum inhibitory concentration (MIC<2ug), favouring its use in treating infections caused by specific pathogens.This systematic review summarises all the reported PK parameters of cefaclor in healthy and diseased subjects in the literature. This data can help practitioners in adjusting cefaclor doses among different diseases and populations to avoid drug interactions and adverse effects.[2]

In other study，pharmacokinetics of cefaclor  were reported as follows.Cefaclor is rapidly and well absorbed when administered orally. After oral administration to healthy adults in the fasting state, the peak plasma concentration is achieved in about one hour and is proportional to the dose. Animal studies indicate that about 95% of an oral dose is absorbed.Mean peak plasma concentrations of approximately 6, 13,and 25 μg/ml are obtained one hour after single oral doses of 250,500,and 1000 mg, respectively. Although bioavailability (as calculated from the area under the plasma concentration time curve) is not affected by food, the peak plasma concentration is delayed to about two hours after administration and is approximately halved if the drug is administered to adults one-half hour after a meal. Similarly,peak concentrations were found to be smaller in children given the drug and milk concomitantly.

The plasma concentration of cefaclor declines rapidly,with no drug detectable in the plasma four to six hours after a single dose. The major route of clearance is urinary excretion; about 70% of the active drug is recovered from the urine within six hours in patients with normal renal function. Cefaclor is apparently not metabilized in the liver.However, because of chemical instability, it degrades topresumably inactive products. In vitro at 37℃, only 10% of the original microbiologically active form is found in plasma after six hours. About 25% of the drug is bound to plasma proteins. The mean plasma half-life in patients with normal renal function is about one hour.Elimination of the drug is slower in patients with renal impairment;the plasma half-life is prolonged to about three hours in the anephric patient, necessitating dosage modification in severe renal impairment.

The average peak concentration of cefaclor in aqueous humor is 0.72 μg/ml and occurs three hours after a 1-g oral dose; this peak is approximately equal to that achieved by cephalexin. This drug concentration does not approach the minimum inhibitory concentration of most organisms that are commonly responsible for bacterial endopbtbalmitis.Although in vivo data appear to be lacking, cefaclor presumably does not cross the blood-brain barrier well.[2] 

References

1.Saleem T, Zamir A, Rasool MF, Imran I, Saeed H, Alqahtani F. Exploring the pharmacokinetics of second-generation cephalosporin, cefaclor: a systematic review in healthy and diseased populations. Xenobiotica. 2024;54(4):171-181. doi:10.1080/00498254.2024.2333009

2.Derry JE. Evaluation of cefaclor. Am J Hosp Pharm. 1981;38(1):54-58.